Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia.

TitleTwo high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia.
Publication TypeJournal Article
Year of Publication2018
AuthorsMcMaster ML, Berndt SI, Zhang J, Slager SL, Li SAlfred, Vajdic CM, Smedby KE, Yan H, Birmann BM, Brown EE, Smith A, Kleinstern G, Fansler MM, Mayr C, Zhu B, Chung CC, Park J-H, Burdette L, Hicks BD, Hutchinson A, Teras LR, Adami H-O, Bracci PM, McKay J, Monnereau A, Link BK, Vermeulen RCH, Ansell SM, Maria A, Diver RW, Melbye M, Ojesina AI, Kraft P, Boffetta P, Clavel J, Giovannucci E, Besson CM, Canzian F, Travis RC, Vineis P, Weiderpass E, Montalvan R, Wang Z, Yeager M, Becker N, Benavente Y, Brennan P, Foretova L, Maynadié M, Nieters A, de Sanjose S, Staines A, Conde L, Riby J, Glimelius B, Hjalgrim H, Pradhan N, Feldman AL, Novak AJ, Lawrence C, Bassig BA, Lan Q, Zheng T, North KE, Tinker LF, Cozen W, Severson RK, Hofmann JN, Zhang Y, Jackson RD, Morton LM, Purdue MP, Chatterjee N, Offit K, Cerhan JR, Chanock SJ, Rothman N, Vijai J, Goldin LR, Skibola CF, Caporaso NE
JournalNat Commun
Volume9
Issue1
Pagination4182
Date Published2018 Oct 10
ISSN2041-1723
Abstract

Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare, chronic B-cell lymphoma with high heritability. We conduct a two-stage genome-wide association study of WM/LPL in 530 unrelated cases and 4362 controls of European ancestry and identify two high-risk loci associated with WM/LPL at 6p25.3 (rs116446171, near EXOC2 and IRF4; OR = 21.14, 95% CI: 14.40-31.03, P = 1.36 × 10) and 14q32.13 (rs117410836, near TCL1; OR = 4.90, 95% CI: 3.45-6.96, P = 8.75 × 10). Both risk alleles are observed at a low frequency among controls (~2-3%) and occur in excess in affected cases within families. In silico data suggest that rs116446171 may have functional importance, and in functional studies, we demonstrate increased reporter transcription and proliferation in cells transduced with the 6p25.3 risk allele. Although further studies are needed to fully elucidate underlying biological mechanisms, together these loci explain 4% of the familial risk and provide insights into genetic susceptibility to this malignancy.

DOI10.1038/s41467-018-06541-2
Alternate JournalNat Commun
PubMed ID30305637
PubMed Central IDPMC6180091
Grant ListHHSN261200800001C / RC / CCR NIH HHS / United States
HHSN261200800001E / CA / NCI NIH HHS / United States
P30 CA086862 / CA / NCI NIH HHS / United States
P50 CA097274 / CA / NCI NIH HHS / United States